This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 115/19/2490    most recent CIRCULATIONAHA.106.667584v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Faraday, N. Articles by Becker, D. M. Search for Related Content PubMed PubMed Citation Articles by Faraday, N. Articles by Becker, D. M. Related Collections Antiplatelets Aggregation Genetics of cardiovascular disease Platelet function inhibitors Platelets

(Circulation. 2007;115:2490-2496.)
© 2007 American Heart Association, Inc.

Genetics

Heritability of Platelet Responsiveness to Aspirin in Activation Pathways Directly and Indirectly Related to Cyclooxygenase-1

Nauder Faraday, MD; Lisa R. Yanek, MPH; Rasika Mathias, PhD; J. Enrique Herrera-Galeano, MS; Dhananjay Vaidya, MBBS, PhD, MPH; Taryn F. Moy, MS; M. Daniele Fallin, PhD; Alexander F. Wilson, PhD; Paul F. Bray, MD; Lewis C. Becker, MD; Diane M. Becker, ScD

From the Department of Anesthesiology/Critical Care Medicine, Division of Cardiac Surgical Intensive Care (N.F.), Department of Medicine, Division of General Internal Medicine (L.R.Y., J.E.H.-G., D.V., T.F.M., D.M.B.), and Department of Medicine, Division of Cardiology (L.C.B.), Johns Hopkins Medical Institutions, Baltimore, Md; Inherited Disease Research Branch, National Human Genome Research Institute/National Institutes of Health, Baltimore, Md (R.M., A.F.W.); Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md (M.D.F.); and Department of Medicine, Division of Hematology, Jefferson Medical College, Philadelphia, Pa (P.F.B.).

Correspondence to Nauder Faraday, MD, 298 Meyer Bldg, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail nfaraday{at}jhmi.edu

Received September 30, 2006; accepted February 23, 2007.

Background— The inability of aspirin (acetylsalicylic acid [ASA]) to adequately suppress platelet function is associated with future risk of myocardial infarction, stroke, and cardiovascular death. Genetic variation is a proposed but unproved mechanism for insufficient ASA responsiveness.

Methods and Results— We examined platelet ASA responsiveness in 1880 asymptomatic subjects (mean age, 44±13 years; 58% women) recruited from 309 white and 208 black families with premature coronary heart disease. Ex vivo platelet function was determined before and after ingestion of ASA (81 mg/d for 2 weeks) with the use of a panel of measures that assessed platelet activation in pathways directly and indirectly related to cyclooxygenase-1, the enzyme inhibited by ASA. The proportion of phenotypic variance related to CHD risk factor covariates was determined by multivariable regression. Heritability of phenotypes was determined with the use of variance components models unadjusted and adjusted for covariates. ASA inhibited arachidonic acid–induced aggregation and thromboxane B₂ production by 99% (P<0.0001). Inhibition of urinary thromboxane excretion and platelet activation in pathways indirectly related to cyclooxygenase-1 was less pronounced and more variable (inhibition of 0% to 100%). Measured covariates contributed modestly to variability in ASA response phenotypes (r²=0.001 to 0.133). Phenotypes indirectly related to cyclooxygenase-1 were strongly and consistently heritable across races (h²=0.266 to 0.762; P<0.01), but direct cyclooxygenase-1 phenotypes were not.

Conclusions— Heritable factors contribute prominently to variability in residual platelet function after ASA exposure. These data suggest a genetic basis for the adequacy of platelet suppression by ASA and potentially for differences in the clinical efficacy of ASA.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				J. E. Herrera-Galeano, D. M. Becker, A. F. Wilson, L. R. Yanek, P. Bray, D. Vaidya, N. Faraday, and L. C. Becker A Novel Variant in the Platelet Endothelial Aggregation Receptor-1 Gene Is Associated With Increased Platelet Aggregability Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1484 - 1490. [Abstract] [Full Text] [PDF]

				L. T. Newsome, M. A. Kutcher, and R. L. Royster Coronary Artery Stents: Part I. Evolution of Percutaneous Coronary Intervention Anesth. Analg., August 1, 2008; 107(2): 552 - 569. [Abstract] [Full Text] [PDF]

				A. Y. Gasparyan, T. Watson, and G. Y.H. Lip The Role of Aspirin in Cardiovascular Prevention: Implications of Aspirin Resistance J. Am. Coll. Cardiol., May 13, 2008; 51(19): 1829 - 1843. [Abstract] [Full Text] [PDF]

				J. E. Freedman Heritability, Platelet Function, and Aspirin: A Link Established but Cause Unknown Circulation, May 15, 2007; 115(19): 2468 - 2470. [Full Text] [PDF]

				D. J. Fitzgerald and A. Maree Aspirin and Clopidogrel Resistance Hematology, January 1, 2007; 2007(1): 114 - 120. [Abstract] [Full Text] [PDF]